Levosimendan, which is the (−)-enantiomer of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]propanedinitrile, and the method for its preparation is described in EP 565546 B1. Levosimendan is potent in the treatment of heart failure and has significant calcium dependent binding to troponin. Levosimendan is represented by the formula: 
The hemodynamic effects of levosimendan in man are described in Sundberg, S. et al., Am. J. Cardiol., 1995; 75: 1061-1066. Pharmacokinetics of levosimendan in man after i.v. and oral dosing is described in Sandell, E. -P. et al., J. Cardiovasc. Pharmacol., 26(Suppl. I), S57-S62, 1995. The use of levosimendan in the treatment of myocardial ischemia is described in WO 93/21921. Clinical studies have confirmed the beneficial effects of levosimendan in heart failure patients.
Oral administration of levosimendan has proved to be difficult, especially when the aim is a therapeutical effect over an extended period of time. Firstly, the elimination half-life of levosimendan in human is short, about 1 h. Therefore, using conventional immediate release oral formulations levosimendan should be administered frequently during the day. Secondly, the gastrointestinal absorption of levosimendan is rapid. Therefore, using immediate release oral formulations high peak plasma concentrations of levosimendan are reached rapidly and abruptly, typically within 1 hour. High plasma concentrations of levosimendan tend to increase heart rate which is an undesired effect in heart failure patients.
Long-acting peroral compositions provide many advantages over conventional peroral rapid release compositions. Such advantages include smaller variation of drug concentrations in plasma and, as a result, steady therapeutic response, reduced frequency of administration and reduction of side effects. Typically long-acting compositions are prepared by mixing the drug, a release controlling agent and possible excipients, and pressing the mixture into matrix tablets. Typical long-acting compositions release drug in the upper as well as in the lower gastrointestinal tract.
Attempts to administer levosimendan in conventional long-acting preparations have been disappointing. Undesired effects such as severe headache, palpitation and increased heart rate are frequently observed when levosimendan is administered in long-acting preparations which are conventionally used in the art to obtain a therapeutical effect over an extended period of time. Therefore there is a need for new methods and compositions for administering levosimendan orally, in particular for methods and compositions which provide a therapeutical effect of levosimendan over an extended period of time and which avoid the drawbacks associated with the conventional long-acting preparations of levosimendan.